The combination of ivuxolimab and utomilumab was well tolerated in patients with advanced solid tumors, according to a phase 1 study.
Ivuxolimab, an OX40 monoclonal antibody, combined with utomilumab, a 4-1BB monoclonal antibody, showed signs of preliminary antitumor activity in patients with advanced solid tumors and was well tolerated, according to the results of phase 1 study (NCT02315066). The study also demonstrated that the investigational combination was well tolerated.
“In this first-in-human study of a novel immunomodulatory combination of the OX40 and 4-1BB agonistic antibodies ivuxolimab and utomilumab, the combination was generally associated with a tolerable safety profile in patients with advanced solid tumors enrolled in the dose-escalation and expansion cohorts, with no DLTs [dose-limiting toxicities] and mostly grade 1 to 2 treatment-related AEs [adverse events],” the study authors, led by Omid Hamid, MD, wrote in their report published in the Journal for ImmunoTherapy of Cancer.
Both OX40 and 4-1BB are part of the tumor necrosis factor receptor superfamily, which impacts T-cell activation, proliferation, and survival.
In preclinical studies, dual activation of OX40 and 4-1BB led to clonal expansion of CD4 and CD8 T cells and cytotoxicity of T cells. Ivuxolimab and utomilumab have both been explored as monotherapies in phase 1 trials but never together. However, each agent has shown the potential to be well tolerated in combination regimens with other immunotherapy agents.
Investigators in this multicenter, open-label study sought to explore the combination’s safety, tolerability, maximum-tolerated dose, and antitumor activity in patients with advanced solid tumors. The study consisted of dose-escalation and a dose-expansion phases, which included a cohort of patients with malignant melanoma and a second cohort of patients with advanced non–small cell lung cancer (NSCLC) who had progressed on prior immune checkpoint inhibitors.
In the dose-escalation phase, adult patients with various advanced solid tumors received varying doses of intravenous ivuxolimab (0.1 mg/kg, 1 mg/kg, or 3 mg/kg administered every 2 weeks) and utomilumab (20 mg or 100 mg administered every 4 weeks) across 5 cohorts. The eligible tumor types included NSCLC, head and neck squamous cell carcinoma (HNSCC), melanoma, urothelial cell carcinoma, gastric cancer, and squamous cell carcinoma of the uterine cervix. All patients had progressed on or were intolerant to standard therapies.
A total of 57 patients were included in the dose-escalation phase and 30 in the dose-expansion phase. Overall, the majority of patients were male, were White, had received prior systemic anticancer therapies, and had a mean age of less than 65 years. In the dose-escalation phase, the most frequent disease type was melanoma (31.6%), followed by HNSCC (21.1%).
In the dose-escalation portion of the study, 2 patients had a partial response (PR), for an objective response rate (ORR) of 3.5%. The PRs were reported in patients with melanoma, 1 in the 0.3-mg/kg ivuxolimab plus 20-mg utomilumab cohort and 1 in the 0.3-mg/kg ivuxolimab plus 100-mg utomilumab cohort. The PR in the patient with metastatic mucosal melanoma, who had previously received ipilimumab (Yervoy) and pembrolizumab (Keytruda), lasted more than 952 days, and the patient remained on treatment as of the data cutoff date. In 18 patients with melanoma, the ORR was 11.1% and the disease control rate was 38.9%.
Stable disease (SD) by RECIST criteria was reported in 18 patients (31.6%). By immune-related RECIST criteria, SD was seen in 45.6% of patients. The longest duration of SD was seen in the 0.3-mg/kg ivuxolimab plus 100-mg utomilumab cohort at 23.9 weeks (range, 11.1-41.9).
Among patients in the dose-expansion NSCLC cohort (n=20), 1 patient had a PR, for an ORR of 5%. SD was reported in 35% of patients with a median duration of 24.0 weeks (range, 13.9-77.9+). By RECIST criteria, the disease control rate was 40% and was 60% by immune-related RECIST criteria.
In the 10 patients in the melanoma cohort, no PRs were reported, but 70% of patients achieved SD with a median duration of 18.9 weeks (range, 13.9-49.0).
Grade 1/2 AEs were reported in 40.4% of patients in the dose-escalation portion of the study, grade 3/4 AEs in 49.1%, and grade 5 events in 10.5%. Seven patients discontinued treatment because of AEs.
In the dose-expansion cohorts, grade 1/2 AEs were observed in 46.7% of patients, grade 3/4 AEs in 36.7%, and grade 5 events in 16.7%. Two patients discontinued treatment because of AEs. The most common treatment-related AEs were pruritus (20.0%), anemia (13.3%), fatigue (13.3%), decreased appetite (10.0%), and rash (10.0%).
No DLTs were reported in any portion of the study, and the combination was considered to have a favorable safety profile. As such, the maximum tolerated dose was not reached.
With escalating doses of the combination regimen, the area under the time curve for ivuxolimab increased in a dose-dependent manner.
A total of 30.6% of 85 evaluable patients had treatment-induced antidrug antibody responses, 2.4% had treatment-boosted antidrug antibody responses, and 2.4% had neutralizing antibodies directed at ivuxolimab, as assessed by electrochemiluminescence assay and cell-based assay. Most of the antidrug antibody responses were transient (67.9%) and observed at lower doses.
Comparatively, among 80 patients evaluable regarding utomilumab, 61.3% had treatment-induced antidrug antibody responses, 6.3% had treatment-boosted antidrug antibody responses, and 57.5% had neutralizing antibodies directed at utomilumab. These antidrug antibody responses were mostly not persistent.
Transcriptional analysis also showed that patients who achieved partial response had upregulation of CD8. The greatest increase in CD8 expression was observed in the patient with NSCLC who had the longest duration of SD.
The study authors noted that further assessment of the combination is ongoing in various studies as well as studies looking at the regimen in combination with other immunotherapy and/or radiation therapies. The potential of these 2 checkpoints will continue to be explored to determine how they can further enhance antitumor activity for patients with cancer.